Dietary polyunsaturated fatty acids (PUFAs) have effects on diverse physiological processes impacting normal health and chronic diseases, such as the regulation of plasma lipid levels, cardiovascular and immune functions, insulin action, and neuronal development and visual function. Ingestion of PUFAs (generally in ester form, e.g. in glycerides or phospholipids) will lead to their distribution to virtually every cell in the body with effects on membrane composition and function, eicosanoid synthesis, cellular signalling and regulation of gene expression. Variations in distribution of different fatty acids/lipids to different tissues in addition to cell specific lipid metabolism, as well as the expression of fatty acid-regulated transcription factors, is likely to play an important role in determining how cells respond to changes in PUFA composition. (Benatti, P. Et al, J. Am. Coll. Nutr. 2004, 23, 281).
PUFAs or their metabolites have been shown to modulate gene transcription by interacting with several nuclear receptors. These are the peroxisome proliferators-activated receptors (PPARs), the hepatic nuclear receptor (HNF-4), liver X receptor (LXR), and the 9-cis retinoic acid receptor (retinoic X receptor, RXR). Treatment with PUFAs can also regulate the abundance of many transcriptional factors in the nucleus, including SREBP, NFκB, c/EBPβ, and HIF-1α. These effects are not due to direct binding of the fatty acid to the transcription factor, but involve mechanisms that affect the nuclear content of the transcription factors.
The regulation of gene transcription by PUFAs have profound effects on cell and tissue metabolism and offer a credible explanation for the involvement of nutrient-gene interactions in the initiation and prevention or amelioration of diseases such as obesity, diabetes, cardiovascular disorders, immune-inflammatory diseases and cancers (Wahle, J., et al, Proceedings of the Nutrition Society, 2003, 349).
Fish oils rich in the ω-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to reduce the risk of cardiovascular diseases partly by reduction of blood triglyceride concentration. This favourable effect mainly results from the combined effects of inhibition of lipogenesis by decrease of SPEBP-1 and stimulation of fatty acid oxidation by activation of PPAR-α in the liver.

ω-3 polyunsaturated fatty acids in fish oil have been reported to improve the prognosis of several chronic inflammatory diseases characterized by leukocyte accumulation and leukocyte-mediated tissue injury, including atherosclerosis, IgA nephropathy, inflammatory bowel disease, rheumatoid arthritis, psoriasis, etc. (Mishra, A., Arterioscler. Thromb. Vasc. Biol., 2004, 1621).
DHA is the most abundant ω-3 PUFA in most tissues and it is highly enriched in neural membranes, constituting approximately 30-40% of the phospholipids of the grey matter of cerebral cortex and photoreceptor cells in the retina. DHA accumulates at high levels in the postnatal mammalian CNS indicating that DHA is involved in the maturation of the CNS. In several different species, decreased levels of DHA in the brain and retina are associated with impairments in neural and visual functions. DHA supplementation may be beneficial in treatment of depression, schizophrenia, hyperactivity, multiple sclerosis, Alzheimer, degenerative retinal diseases, and peroxisomal disorders. (Horrocks and Farooqui, Prostaglandins, Leukotrienes and Essential Fatty acids, 2004, 70, 361). Dietary DHA may also be beneficial in treatment of atherosclerosis, inflammation and cancer (Horrocks et al, Pharmacol Res 1999, 40: 211; Rose, et al, 1999, 83, 217).
Although ω-3 PUFAs possess many positive biological effects, their therapeutic value has been limited and the therapeutic area where the ω-3 PUFAs have been most promising is in the cardiovascular field as a triglyceride lowering agent. However, high doses of polyunsaturated fatty acids are necessary to cause hypolipidemia. One reason for this is degradation of the polyunsaturated fatty acids in liver by oxidation.
Nuclear receptors (NRs) constitute a large and high conserved family of ligand activated transcriptional factors that regulate diverse biological processes such as development, metabolism, and reproduction. It is recognised that ligands for these receptors might be used in the treatment of common diseases such as atherosclerosis, diabetes, obesity, and inflammatory diseases. As such, NRs have become important drug targets, and the identification of novel NR ligands is a subject of much interest. The activity of many nuclear receptors is controlled by the binding of small, lipophilic ligands that include hormones, metabolites such as fatty acids, bile acids, oxysteroles and xeno- and endobiotics. Nuclear receptors can bind as monomers, homodimers, or RXR heterodimers to DNA. Three types of heterodimeric complexes exist: unoccupied heterodimers, nonpermissive heterodimers that can be activated only by the partners ligand but not by an RXR ligand alone, and permissive heterodimers that can be activated by ligands of either RXR or its partner receptor and are synergistically activated in the presence of both ligands (Aranda and Pascual, Physiological Reviews, 2001, 81, 1269). As the obligate heterodimer partner for many nuclear receptors (including the vitamin D receptor (VDR), thyroid hormone receptor (TR), all-trans retinoic acid receptor (RAR), peroxisome proliferator-activated receptor (PPAR), liver-X receptor (LXR) and others) RXR plays the role of a master co-ordinator of multiple nuclear receptor pathways.
The ligands that regulate RXR heterodimer partners can roughly be divided into two subsets. One subset comprises high affinity, highly specific steroid/hormone ligands (VDR and TR) and act as endocrine modulators. The other subset binds to abundant, lower affinity lipid ligands (PPAR, LXR) and appears to act in part as lipid biosensors. The genes regulated by the RXR heterodimers include those involved in a wide variety of cellular processes including cell-cycle regulation and differentiation. They also regulate genes involved in lipid transport, biosynthesis, and metabolism (Goldstein, J. T. et al, Arch. Biochem and Biophys., 2003, 420, 185).
The cognate ligand of RXR is 9-cis-retinoic acid, a molecule that also binds and transactivates RAR with very similar affinity and efficiency. On the other hand all-trans-retinoic acid, the cognate ligand of RAR, does not bind to the RXR receptor.

Evidence has been provided that RXR ligands can function as insulin sensitizers and can decrease hyperglycaemia, hyperinsulinaemia and hypertriglyceridaemia in ob/ob and db/db mice (Mukherjee et al, Nature, 1997, 386, 407). It has also been published that chronic administration of RXR agonists to Zucker fa/fa rats reduces food intake and body weight gain, lowers plasma insulin concentrations while maintaining normoglycaemia (Liu, et al, Int. J. Obesity., 2000, 997; Ogilvie, K. et al, Endocrinology, 2004, 145, 565).
In 2000 it was published that DHA isolated from mice brain selectively activated RXR in cell-based assays (Urquiza et al, Science 2000, 290, 2140, WO 01/73439). In this study DHA did not activate RAR. Since then it has been published that several unsaturated fatty acids, including DHA, arachidonic acid, and oleic acid, have the capacity to specifically bind and activate the RXRα LBD (ligand binding domain) and thereby act as in vivo ligands for this receptor. (Lengquist J., et. al. Molecular & Cellular Proteomics 3, 2004, 692). In a study published by Fan et al, it was shown that DHA serve as a specific ligand for RXRα activation relative to n-6 PUFA in colonocytes (Carcinogenesis, 2003, 24, 1541).
Although RXR agonists are known and the compounds have been tested in different biological systems, the prior art does not describe the use of modified PUFAs as potent ligands for RXR.
The transcription factor NF-κB is an inducible eukaryotic transcription factor of the rel family. It is a major component of the stress cascade that regulate the activation of early response genes involved in the expression of inflammatory cytokines, adhesion molecules, heat-shock proteins, cyclooxygenases, lipoxygenases, and redox enzymes. Zhao, G. et al (Biochemical and Biophysical Research Comm., 2005, 909) suggest that the anti-inflammatory effects of PUFAs in human monocytic THP-1 cells are in part mediated by inhibition of NF-κB activation via PPAR-γ activation. Others have suggested that the anti-inflammatory effect of PUFAs is mediated through a PPAR-α dependent inhibition of NF-κB activation.
Receptor-selective ligands are a high priority in the search for NR-based drug leads, since native NR ligands present systemic side effects and toxicity due to their lack of binding specificity.
9-cis Retinoic acid regulates a wide variety of biological functions through a mechanism that entails binding to both RXR and RAR. These receptors are involved in many different functions. Their far reaching biological effects have motivated the search for RAR- or RXR-selective ligands. Non selective retinoid ligands when employed as drugs have side effects such as teratogenicity and mucocutaneously toxicity, which are significantly reduced when specific RXR agonists are used. Furthermore, it has been shown that tumour-specific apoptosis can be driven by RXR-selective agonists. Selective RXR agonists may offer an alternative approach for the treatment of metabolic disorders. There is thus a need for easily accessible RXR-selective ligands which may provide the above-mentioned benefits without the side effects of non-selective ligands.
Because many of the nuclear receptors are distributed differently in different tissues it is important to make ligands that in vivo are able to target specified cells in order to bind and activate the target receptor.